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At least 1,621 records · Page 90Linked to original sources
PubMed2002

Hepatocyte nuclear factor-1alpha modulates pancreatic beta-cell growth by regulating the expression of insulin-like growth factor-1 in INS-1 cells.

Maturity-onset diabetes of the young type 3 (MODY3) is characterized by impaired insulin secretion. Heterozygous mutations in the gene encoding hepatocyte nuclear factor (HNF)-1alpha are the cause of MODY3. Transgenic mice overexpressing dominant-negative HNF-1alpha mutant in pancreatic beta-cells and HNF-1alpha knockout mice are animal models of MODY3. These mice exhibit defective glucose-stimulated insulin secretion and have reduced beta-cell mass and beta-cell proliferation rate. Here we examined the effect of HNF-1alpha on beta-cell proliferation by overexpressing a human naturally occurring dominant- negative mutation P291fsinsC in INS-1 cells under the control of doxycycline-induction system. INS-1 cells overexpressing P291fsinsC showed apparent growth impairment. The proliferation rate estimated by [(3)H]thymidine incorporation was significantly reduced in P291fsinsC-expressing INS-1 cells compared with noninduced or wild-type HNF-1alpha-overexpressing INS-1 cells. Growth inhibition occurred at the transition from G1 to S cell cycle phase, with reduced expression of cyclin E and upregulation of p27. cDNA array analysis revealed that the expression levels of IGF-1, a major growth factor for beta-cells, and macrophage migration inhibitory factor (MIF), a cytokine expressed in pancreatic beta-cells, were reduced in P291fsinsC-HNF-1alpha-expressing INS-1 cells. Although MIF seemed to have proliferative function, blockade of MIF action by anti-MIF antibody stimulated INS-1 cell proliferation, excluding its direct role in the growth impairment. However, addition of IGF-1 to P291fsinsC-expressing INS-1 cells rescued the growth inhibition. Our data suggest that HNF-1alpha is critical for modulating pancreatic beta-cell growth by regulating IGF-1 expression. IGF-1 might be a potential therapeutic target for the treatment of MODY3.

Animals↗
PubMed1987

Defective glucose utilization in patients with functioning beta-cell tumors persists after tumor excision.

Glucose utilization was assessed before and after operation in five patients with insulin-secreting tumors using the euglycemic clamp. Two groups of age, sex, and weight-matched controls were studied under conditions of either acute (3 h, N = 7) or chronic (48-72 h, N = 6) hyperinsulinemia (46 +/- 4 microU/mL). The rate of glucose infusion (M = mg/kg/min) required to maintain steady-state euglycemia was taken as index of glucose utilization. M was higher both in postoperative patients and in chronic controls than in preoperative patients (2.1 +/- 0.1 and 1.8 +/- 0.2 vs. 1.0 +/- 0.2, p less than 0.01), yet never achieved levels seen in acute controls (3.3 +/- 0.3, p less than 0.01). Also reported is one subject who had a predominantly proinsulin-producing tumor with little insulin secretion, who also manifested a similar defect in glucose utilization. Excision of this tumor resulted in partial reversal of the peripheral defect in glucose metabolism. In conclusion, chronic endogenous hyperinsulinemia (and hyperproinsulinemia) in humans is associated with a defect in peripheral glucose utilization that is only partially resolved 2 years after tumor removal.

Adenoma, Islet Cell↗
PubMed2005

Interaction of myocilin with gamma-synuclein affects its secretion and aggregation.

Mutations in the gene encoding human myocilin are associated with some cases of juvenile and early-onset glaucoma. Glaucomatous mutations prevent myocilin from being secreted. The analysis of the defects associated with mutations point to the existence of factor(s) in addition to mutations that might be implicated in the development of glaucoma. In the present paper, we found that interaction of myocilin with one of the members of the synuclein family alters its properties, including its ability to be secreted. Results of immunoprecipitation show that myocilin is a gamma-synuclein-interacting protein. Further analysis demonstrated that both myocilin and gamma-synuclein are expressed in human TM cells, immortalized rat ganglion (RGC-5) cells, and HT22 hippocampal neurons. According to Western blotting, in addition to monomeric form with molecular weight 17 kDa gamma-synuclein is present as higher molecular weight forms ( approximately 35 and 68 KDa), presumably dimer and tetramer. Myocilin and gamma-synuclein have partially overlapping perinuclear localization. Dexamethasone upregulates myocilin expression in RGC-5 cells and HT22 hippocampal neurons. We found alterations of myocilin properties as a result of its interaction with gamma-synuclein. In cultured cells, gamma-synuclein upregulates myocilin expression, inhibits its secretion and prevents the formation of high molecular weight forms of myocilin. Although both alpha-synuclein and gamma-synuclein are expressed in HTM cells, only gamma-synuclein interacts with myocilin and alters its properties. We conclude that myocilin and gamma-synuclein interact and as a result, myocilin's properties are changed. Since myocilin and gamma-synuclein have partially overlapping intracellular localization in cell types that are implicated in glaucoma development, their interaction may play an important role in glaucoma.

Adolescent↗
PubMed1975

Pathophysiology of Shigella diarrhea in the rhesus monkey: intestinal transport, morphological, and bacteriological studies.

In contrast to the "toxigenic diarrheas" caused by Vibrio cholerae and Escherichia coli, the site and mechanism of fluid loss in shigellosis are unknown. The occurrence of watery diarrhea in shigellosis suggests involvement of the small bowel. Therefore, jejunal, ileal, and colonic water and electrolyte transport was studied in Shigella flexneri 2a-infected monkeys. Infected animals fell into three groups: dysentery alone, diarrhea alone, or diarrhea and dysentery. In controls, net water, sodium, and chloride absorption was seen in the jejunum, ileum, and colon. All infected animals demonstrated diminished colonic absorption or net colonic secretion. In monkeys with dysentery alone, this was the only transport defect observed. In contrast, animals with diarrhea either alone or in combination with dysentery, exhibited net jejunum secretion. Ileal transport was normal in all animals. A severe colitis with intramucosal shigellae was seen in all symptomatic animals. In the jejunum or ileum, however, morphological changes were minimal and bacterial invasion was not seen. Therefore, unlike the "toxigenic" diarrheas," shigellosis is both a small and large intestinal disease. Mucosal invasion of the colon is essential to the development of a morphological and transport defect. Dysentery results from a colonic transport defect, while diarrhea is secondary to jejunal secretion superimposed on the defect in colonic absorption.

Animals↗
PubMed1986

Effect of cholinergic muscarinic receptor blockade on human growth hormone (GH)-releasing hormone-(1-44)-induced GH secretion in acromegaly and type I diabetes mellitus.

In 10 patients with type I diabetes mellitus, 9 acromegalic patients, and 8 normal subjects, serum GH levels after an iv injection of 1 microgram/kg BW human GH-releasing hormone-(1-44) (GHRH) with and without cholinergic muscarinic receptor blockade (1 mg atropine, im, 15 min before GHRH) were measured. The GH increase after GHRH treatment in type I diabetic patients did not differ significantly from that in normal subjects. Pretreatment with atropine almost completely blocked the GH response to GHRH in patients with type I diabetes and normal subjects, but did not suppress the GH response to GHRH in acromegalic patients. These data indicate that cholinergic muscarinic receptors modulate GH secretion in normal man as well as in patients with type I diabetes mellitus, whereas acromegalic patients have a defect of cholinergic control of GH secretion.

Acromegaly↗
PubMed1981

Characterization of genetic defects in macrophage tumoricidal capacity: identification of murine strains with abnormalities in secretion of cytolytic factors and ability to bind neoplastic targets.

Peritoneal macrophages from BCG-infected C3H/HeJ or A/J mice, in contrast to BCG-activated macrophages from C3H/HeN mice, were ineffective at lysing adherent 1023 sarcoma targets, nonadherent P815 mastocytoma targets, or nonadherent EL-4 lymphoma targets. The ability of macrophages from BCG-infected C3H/HeJ mice to secret cytolytic factor (CF) into the supernatant medium was markedly impaired. This secretory deficit, however, did not extend to plasminogen activator, secretion of which was augmented. In contrast, the ability of BCG macrophages from A/J mice to secrete CF was comparable to or even slightly higher than that of macrophages from C3H/HeN mice. The ability of BCG-elicited macrophages from A/J mice to bind either of 2 neoplastic targets (the P815 mastocytoma and the EL-4 lymphoma), however, was greatly reduced. The ability of BCG-elicited macrophages from C3H/HeJ mice to bind these targets was comparable to that of macrophages from C3H/HeN mice. The data suggest that the phenotypically-similar deficits in tumoricidal capacity of BCG-elicited macrophages from C3H/HeJ and A/J mice are mediated by mechanistically different defects in macrophage-tumor cell interactions.

Animals↗
PubMed2003

Virulence systems of Pseudomonas syringae pv. tomato promote bacterial speck disease in tomato by targeting the jasmonate signaling pathway.

Pseudomonas syringae pv. tomato strain DC3000 (Pst DC3000) causes bacterial speck disease on tomato. The pathogenicity of Pst DC3000 depends on both the type III secretion system that delivers virulence effector proteins into host cells and the phytotoxin coronatine (COR), which is thought to mimic the action of the plant hormone jasmonic acid (JA). We found that a JA-insensitive mutant (jai1) of tomato was unresponsive to COR and highly resistant to Pst DC3000, whereas host genotypes that are defective in JA biosynthesis were as susceptible to Pst DC3000 as wild-type (WT) plants. Treatment of WT plants with exogenous methyl-JA (MeJA) complemented the virulence defect of a bacterial mutant deficient in COR production, but not a mutant defective in the type III secretion system. Analysis of host gene expression using cDNA microarrays revealed that COR works through Jai1 to induce the massive expression of JA and wound response genes that have been implicated in defense against herbivores. Concomitant with the induction of JA and wound response genes, the type III secretion system and COR repressed the expression of pathogenesis-related (PR) genes in Pst DC3000-infected WT plants. Resistance of jai1 plants to Pst DC3000 was correlated with a high level of PR gene expression and reduced expression of JA/wound response genes. These results indicate that COR promotes bacterial virulence by activating the host's JA signaling pathway, and further suggest that the type III secretion system might also modify host defense by targeting the JA signaling pathway in susceptible tomato plants.

Amino Acids↗
PubMed1977

Impaired renal tubular potassium secretion in systemic lupus erythematosus.

Two patients with long-standing systemic lupus erythematosus were found to have persistent hyperkalemia. The hyperkalemia could not be explained by renal insufficiency, oliguria, diminished distal sodium delivery, acidemia, or hemolysis. After sodium depletion, urinary aldosterone excretion and plasma aldosterone concentration rose appropriately. No increase in urinary potassium excretion or decrease in serum potassium concentration was noted after fludrocortisone acetate, furosemide, or acetazolamide plus sodium bicarbonate. We conclude that these patients have a primary defect in renal tubular potassium secretion that may be related to an immune complex interstitial nephritis.

Acetazolamide↗
PubMed1976

Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency.

Hypocalcaemia is a well-recognized manifestation of magnesium deficiency. We have studied seventeen patients with this syndrome in an attempt to determine the pathogenesis of the hypocalcaemia. Mean initial serum calcium concentration was 5-6 mg/dl and mean initial serum magnesium concentration was 0-75 mg/dl. Serum immunoreactive parathyroid hormone (IPTH) was measured in sixteen patients in the untreated state. Despite severe hypocalcaemia, serum IPTH was either undetectable (less than 150 pg/ml) or normal (less than 550 pg/ml) in all but two patients. Serial measurements made during the initial 4 days of magnesium therapy in four patients showed an increase in serum IPTH within 24h, but a delayed increase in serum calcium, which required approximately 4 days to reach normal values. The effect of the rapid normalization of serum magnesium on serum IPTH and serum calcium concentration was studied in three patients. Within 1 min after 144-300 mg of elemental magnesium was administered i.v., serum IPTH had risen from undetectable to 3600 pg/ml and 1725 pg/ml in two patients and from 425 pg/ml to 937 pg/ml in the third. Serum calcium concentrations were unchanged after 30-60 min. These data provide evidence for impaired parathyroid gland function in most of the magnesium deficient patients. The rapidity with which serum IPTH rose in response to magnesium therapy indicates that this may reflect a defect in parathyroid hormone (PTH) secretion rather than its biosynthesis. The failure of serum calcium concentration to increase during the initial days of magnesium repletion, at a time when serum IPTH concentrations were normal or elevated, suggests end-organ resistance to PTH in these patients. The renal response to PTH was examined in two magnesium deficient patients by measurement of urinary cyclic AMP excretion following administration of parathyroid extract. In both patients there was a minimal increase in urinary cyclic AMP concentrations. In contrast, when the hepatic response to glucagon was tested on the same patients by measurement of plasma cyclic AMP concentrations following administration of glucagon, normal increases were observed. These results suggest that adenylate cyclase systems of various organs may be affected differentially by a state of magnesium deficiency. It is suggested that magnesium deficiency may result in defective cyclic AMP generation in the parathyroid glands and in the PTH target organs. This could be the principal mechanism operative in both impaired PTH secretion and end-organ resistance to PTH which together contribute to the development of hypocalcaemia.

Adult↗
PubMed1987

Dietary sugars and carbohydrate metabolism in type II diabetes.

Diabetes, the most common metabolic disease, is responsible for the deaths of over 300,000 Americans annually. The incidence of the disease increases with age and since the U.S. population is graying, prevalence is also increasing. Obesity and family history are strong predictors of diabetes. The etiology of Type II diabetes is heterogeneous. The hyperglycemia of Type II diabetes can result from a variety of metabolic defects including impaired beta cell secretion, receptor deficiencies, or abnormal hepatic production or uptake of glucose. Other glucoregulatory hormones such as glucagon, growth hormone, cortisol, thyroid hormones, somatostatin, and gastric inhibitory polypeptide may contribute to the aberrations of carbohydrate metabolism. Environmental factors including stress, diet, and exercise may also contribute to the disease. Since most diabetics are obese, weight loss should be the first priority in improving status. A variety of diet and exercise regimens may help achieve this goal or even improve glucose control without weight loss. Due to the heterogeneity of the disease individualized treatment must be used to improve status of patients with the various metabolic defects of Type II diabetes.

Adult↗
PubMed2005

Glibenclamide stimulates fluid secretion in rodent cholangiocytes through a cystic fibrosis transmembrane conductance regulator-independent mechanism.

BACKGROUND & AIMS: Progressive liver disease is a severe complication of cystic fibrosis, a genetic disease characterized by impaired epithelial adenosine 3',5'-cyclic monophosphate-dependent secretion caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In the liver, CFTR is expressed in cholangiocytes and regulates the fluid and electrolyte content of the bile. Glibenclamide, a sulfonylurea and a known CFTR inhibitor, paradoxically stimulates cholangiocyte secretion. We studied the molecular mechanisms underlying this effect and whether glibenclamide could restore cholangiocyte secretion in cystic fibrosis. METHODS: NRC-1 cells, freshly isolated rat cholangiocytes, isolated rat biliary ducts, and isolated biliary ducts from CFTR-defective mice (Cftr tm1Unc ) were used to study fluid secretion (by video-optical planimetry), glibenclamide-induced secretion (by high-performance liquid chromatography in cell culture medium), intracellular pH and intracellular Ca 2+ concentration transients [2'7'-bis(2-carboxyethyl)-5,6,carboxyfluorescein-acetoxymethylester and Fura-2 f-AM (5-Oxazolecarboxylic acid, 2-(6-(bis(2-((acetyloxy)methoxy)-2-oxoethyl)amino)-5-(2-(2-(bis(2-((acetyloxy)methoxy)-2-oxoethyl)amino)-5-methylphenoxy)ethoxy)-2-benzofuranyl)-, (acetyloxy)methyl ester) microfluorometry], gene expression (by reverse-transcription polymerase chain reaction), and changes in membrane capacitance (by patch-clamp experiments). RESULTS: Stimulation of cholangiocyte secretion by glibenclamide and tolbutamide required Cl - and was mediated by the sulfonylurea receptor 2B. Glibenclamide-induced secretion was blocked by inhibitors of exocytosis (colchicine, wortmannin, LY294002, and N -ethylmaleimide) and by inhibitors of secretory granule acidification (vanadate, bafilomycin A1, and niflumic acid) but was Ca 2+ and depolarization independent; membrane capacitance measurements were consistent with stimulation of vesicular transport and fusion. Glibenclamide, unlike secretin and forskolin, was able to stimulate secretion in Cftr tm1Unc mice, thus indicating that this secretory mechanism was preserved. CONCLUSIONS: The ability of glibenclamide to stimulate secretion in CFTR-defective mice makes sulfonylureas a model class of compounds to design drugs useful in the treatment of cystic fibrosis with liver impairment and possibly of other cholestatic diseases.

ATP-Binding Cassette Transporters↗
PubMed1981

Abnormal regulation of prolactin secretion after successful surgery for prolactin-secreting pituitary tumours.

Patients with prolactin-secreting pituitary tumours have a diminished prolactin (PRL) response after administration of a variety of stimulatory agents, including thyrotrophin-releasing hormone (TRH), chlorpromazine (CPZ) and insulin-induced hypoglycaemia. We examined responses to these agents in sixty-seven women with PRL-secreting tumours before and after trans-sphenoidal surgery. Twenty-nine of the women were cured as defined by restoration of normal serum PRL concentrations and resumption of regular menses. One year following trans-sphenoidal surgery, patients with normal PRL concentrations and regular menses had normal PRL responses to TRH, while the responses to CPZ and insulin hypoglycaemia were not improved. The reversible impairment of PRL response to TRH reflects suppressed function of normal PRL-secreting cells, and the persistence of abnormal PRL responses to provocative stimuli after successful tumour removal may reflect some fundamental defect in the regulation of PRL secretion in patients with PRL-secreting adenomas. When growth hormone (GH) reserve after insulin hypoglycaemia was represented as the mean absolute increment above the basal concentration and compared with normal subjects, women with PRL-secreting tumours had a diminished response that returned to normal after successful surgery. This reversible impairment of GH secretion is not adequately reflected by standard criteria for GH response and suggests that PRL may have a role in the regulation of GH secretion.

Adenoma↗
PubMed1983

Tubero-infundibular dopaminergic function in cirrhotic patients: evaluation by nomifensine and domperidone.

Cirrhotic patients reportedly show alterations of anterior pituitary hormone secretion, which may reflect an underlying defective central neurotransmitter function. In this study, we have investigated the catecholaminergic control of prolactin (Prl) and growth hormone (GH) secretion in cirrhotic patients by means of an indirectly acting dopamine (DA) and norepinephrine agonist, nomifensine (Nom), and a DA receptor antagonist, domperidone (Dom). Basal GH levels were higher in the 12 female and male cirrhotic patients than in the 12 age- and sex-matched normal controls, while no difference was present in basal Prl values. Administration of Nom (200 mg po) suppressed basal Prl levels (at least 30% inhibition at three consecutive times post-drug administration) in 6/12 controls and in 6/12 cirrhotic patients, the frequency of negative responses not being different between the two groups. Nom induced a slight elevation of GH levels in controls, and evoked a more marked and sustained GH increase in cirrhotic patients. Administration of Dom (4 mg iv) induced similar Prl increments in 6 male controls and 6 male cirrhotic patients. Normal Prl responsiveness to Nom and Dom points to the existence of preserved tubero-infundibular DA function and modulation of pituitary DA receptors in the cirrhotic patients investigated. Higher GH responsiveness to Nom is compatible with a different bioavailability of the drug.

Adult↗
PubMed1989

Responsiveness of systemic lupus erythematosus T cells to signals provided through LCA T200 (CD45) and T1 (CD5) antigens.

It is currently unclear whether the T cell defective capacity to proliferate and to secrete interleukin-2 (IL-2) observed in systemic lupus erythematosus (SLE) reflects an intrinsic disorder of the T cell or defects secondary to a monocyte dysfunction. In order to clarify whether the disorder is intrinsic to the T cell, we have studied the proliferative capacity of cells highly depleted of monocytes, activated by Seph-CD3, as 'first signal,' and by monoclonal antibodies (MoAbs) CD45 and CD5 as 'second signal,' in 14 SLE patients. There were no significant differences between SLE patients and healthy volunteers in the response of the monocyte-depleted cells to Seph-CD3+CD45; Seph-CD3+CD5; Seph-CD3+IL-2; and Seph-CD3+phorbol myristate acetate (PMA). However, active SLE compared with non-active SLE had an impaired response of peripheral blood mononuclear cells (PBMC) to Seph-CD3 and to Seph-CD3+IL-2. The good responses obtained to second signals provided through CD45 and CD5 indicate that at least these mechanisms are not intrinsically impaired in SLE T cells. These findings, together with the abnormal response of PBMC suggest that a monocyte dysfunction plays an important role in SLE T cells hyporesponsiveness.

Adolescent↗
PubMed1996

Clinical phenotypes, insulin secretion, and insulin sensitivity in kindreds with maternally inherited diabetes and deafness due to mitochondrial tRNALeu(UUR) gene mutation.

An A-to-G transition in the mitochondrial tRNALeu(UUR) gene at base pair 3243 has been shown to be associated with the maternally transmitted clinical phenotype of NIDDM and sensorineural hearing loss in white and Japanese pedigrees. We have detected this mutation in 25 of 50 tested members of five white French pedigrees. Affected (mutation-positive) family members presented variable clinical features, ranging from normal glucose tolerance (NGT) to insulin-requiring diabetes. The present report describes the clinical phenotypes of affected members and detailed evaluations of insulin secretion and insulin sensitivity in seven mutation-positive individuals who have a range of glucose tolerance from normal (n = 3) to impaired (n = 1) to NIDDM (n = 3). Insulin secretion was evaluated during two experimental protocols: the first involved the measurement of insulin secretory responses during intravenous glucose tolerance test, hyperglycemic clamp, and intravenous injection of arginine. The second consisted of the administration of graded and oscillatory infusions of glucose and studies to define C-peptide kinetics. This protocol was aimed at assessing two sensitive measures of beta-cell dysfunction: the priming effect of glucose on the glucose-insulin secretion rate (ISR) dose-response curve and the ability of oscillatory glucose infusion to entrain insulin secretory oscillations. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Evaluation of insulin secretion demonstrated a large degree of between- and within-subject variability. However, all subjects, including those with NGT, demonstrated abnormal insulin secretion on at least one of the tests. In the four subjects with normal or impaired glucose tolerance, glucose failed to prime the ISR response, entrainment of ultradian insulin secretory oscillations was abnormal, or both defects were present. The response to arginine was always preserved, including in subjects with NIDDM. Insulin resistance was observed only in the subjects with overt diabetes. In conclusion, the pathophysiological mechanisms responsible for the development of NIDDM and insulin-requiring diabetes in this syndrome are complex and might include defects in insulin production, glucose toxicity, and insulin resistance. However, our data suggest that a defect of glucose-regulated insulin secretion is an early possible primary abnormality in carriers of the mutation. This defect might result from the progressive reduction of oxidative phosphorylation and implicate the glucose-sensing mechanism of beta-cells.

Adenine↗
PubMed1990

Inheritance of diabetes mellitus as consequence of gestational hyperglycemia in rats.

Our study investigated whether a deterioration of glucose homeostasis and insulin secretion in adult female rats from hyperglycemic dams could be transmitted to the next generation independent of genetic interferences. Dams (F0) were rendered hyperglycemic by continuous glucose infusion during the last week of pregnancy. Females born of these rats (F1) exhibited glucose intolerance and impaired insulin secretion in vivo at adulthood. When they were 3 mo old, they were matched with males born of control dams. During pregnancy, their glucose tolerance remained impaired compared with that of controls. Consequently, F2 newborns of F1 hyperglycemic dams showed the main features of newborns from diabetic mothers: they were hyperglycemic, hyperinsulinemic, and macrosomic. As adults, they displayed basal hyperglycemia and defective glucose tolerance and insulin secretion. This indicates that the long-range deteriorating effects on glucose homeostasis of gestational hyperglycemia in the F1 generation are transmitted to the F2 generation and suggests that a perturbed fetal metabolic environment contributes to the inheritance of diabetes mellitus.

Animals↗
PubMed2003

Platelet function disorders.

Platelet function disorders are a rare cause of bleeding in hematological practice. The inherited variety includes defects in platelet adhesion, aggregation, secretion and platelet procoagulant activities. The clinical presentation is usually mild with mainly mucocutaneous bleeds. Milder phenotypes may pass off unrecognized in childhood and present later in life. Testing includes a coagulation screen, which may show a prolonged bleeding time, followed by platelet aggregation tests with agonists. Flow cytometry for platelet surface markers, membrane glycoprotein analysis and facilities for identification of the genetic defect are usually available in research laboratories. Recent advances have opened vistas for antenatal testing. Bone marrow transplantation is the only curative therapeutic option available.

Blood Platelet Disorders↗
PubMed2005

Glucose intolerance in young TallyHo mice is induced by leptin-mediated inhibition of insulin secretion.

The pathophysiology of TallyHo mouse, a recently established animal model for type 2 diabetes mellitus, was analyzed at prediabetic state to examine the inherent defects which contribute to the development of diabetes. At 4 weeks of age, the TallyHo mice already revealed glucose intolerance while their peripheral tissues exhibited normal insulin sensitivity. On the other hand, decreased plasma insulin concentration was observed with little differences in pancreatic insulin contents, indicating the impaired insulin secretion. Such defect, however, was not found in the isolated islets, which suggests a role of endocrine factor in impaired insulin secretion of TallyHo mice. Treatment of leptin inhibited the glucose-stimulated insulin secretion from the isolated islets of TallyHo mice, while in vivo administration of anti-leptin antibody lowered plasma glucose concentration with increased insulin level in TallyHo mice. Expression of glucokinase mRNA was decreased both in whole pancreas and leptin treated islets of TallyHo mice compared with whole pancreas in C57BL/6 mice and untreated islets of TallyHo mice, respectively. These results suggest that elevated plasma leptin can, through the inhibition of insulin secretion, induce glucose intolerance in TallyHo mice.

Animals↗